This award will prepare the principal investigator for a career as an independent investigator in Infectious Disease epidemiology, with a particular focus on the clinical outcomes of hepatitis C virus (HCV) infection in those co-infected with HIV. The training component of this proposal will include: 1) advanced epidemiologic coursework at the Center for Clinical Epidemiology and Biostatistics at Penn leading to a Ph.D. in Epidemiology, 2) mentorship from an internationally recognized epidemiologist, 3) collaboration with researchers at Penn in HIV epidemiology, chronic HCV infection, and biostatistics, and 4) collaboration with investigators from two ongoing HIV cohort studies. HCV co-infection is highly prevalent among HIV-infected patients, and end-stage liver disease (ESLD), the main clinical outcome of HCV infection, now represents the major cause of morbidity and mortality among HIV patients in the developed world. Despite the high prevalence of HIV/HCV co-infection and impact of ESLD, the risk factors for this clinical outcome have not been well examined among HIV/HCV patients. Published studies have evaluated primarily predictors of histological outcomes, but few HIV/HCV patients undergo liver biopsy because they refuse or are not offered due to contraindications (e.g., active alcohol use or coagulopathy). These studies are therefore unable to determine accurately the true effects of relevant risk factors for liver disease progression among HIV/HCV patients. In contrast, studies focused on a clinical outcome such as ESLD are far preferable because they can include the typical patients with HIV/HCV co-infection. Since data show that liver disease progression is substantially slower in women versus men, the risk factors and predictors of ESLD are likely to be different in HIV/HCV-co-infected women than in men and should be examined separately. To begin to address these issues, this proposal has three Specific Aims: 1) To determine the risk factors for ESLD among HIV/HCV-co-infected men, 2) To derive and internally validate a clinical predictive index to stratify HIV/HCV-co-infected men by risk of progression to ESLD, and 3) To validate the ability of specified combinations of clinical, laboratory, and pharmacy data collected by the Women's Interagency HIV Study to identify HIV/HCV-co-infected women with ESLD. Specific Aims 1 and 2 will utilize data from the Veterans Aging Cohort Study, a multi-center, prospective cohort study of HIV-positive and -negative veterans in care at eight Veterans Administration medical centers. Specific Aim 3 will utilize data from three sites in the Women's Interagency HIV Study, a prospective cohort study of HIV-positive and -negative women. Upon completion of these aims, the PI will have made substantive contributions to knowledge of the natural history and risk factors for HCV co-infection in HIV-infected men and be poised to make similar contributions in the future to knowledge of the natural history of HCV co-infection in HIV-infected women.